Use of KIF18a inhibitor in treatment of non-small cell lung cancer

Abstract

The use of a KIF18A inhibitor in the preparation of a drug for treating lung cancer (e.g., non-small cell lung cancer) diseases. It is verified in pharmacological experiments that compound 1 or compound 2 can inhibit the growth of non-small cell lung cancer xenografts. Compared with AMG650, compound 1 or compound 2 has a lower drug exposure which can reduce the potential drug cumulative toxicity. It is shown that compound 1 or compound 2 has significant therapeutic effects on non-small cell lung cancer.

Description

Uses of KIF18A inhibitors in the treatment of non-small cell lung cancer

[0001] This application requires the applicant to have:

[0002] The priority right of the prior application filed with the China National Intellectual Property Administration on June 28, 2024, with patent application number 202410864912.7 entitled "Use of KIF18A inhibitor in the treatment of non-small cell lung cancer", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the pharmaceutical field, specifically relating to the use of a KIF18A inhibitor in the preparation of a drug for treating lung cancer (non-small cell lung cancer). Background Technology

[0004] Cancer is one of the most serious diseases affecting human health, with mortality and morbidity rates often ranking among the highest of all diseases. Although the quality of life for some patients has been greatly improved with the continuous development and progress of medical technology and drug research, there are still many unmet clinical needs in the search for effective treatments or cures for different cancers, and new targets will provide new possibilities for future cancer drug development.

[0005] Cancer cells exhibit unregulated cell proliferation due to damage or loss of one or more genes that regulate the cell cycle. Various kinases and kinesins have been identified as playing key roles in the regulation and progression of cell cycle and mitosis in both normally dividing cells and cancer cells.

[0006] Kinesin molecules are kinetic proteins that use intracellular microtubules as their orbital pathways; also known as molecular motors, they convert ATP energy into mechanical energy and are closely related to eukaryotic cell division, mitosis, meiosis, tissue and organ growth and development, neuronal development, and signal transduction. Kinesin members share a relatively conserved motor domain. Based on the location of the motor domain in the molecule, the kinesin family is broadly divided into three categories: N-type kinesins, where the amino (-NH2) terminal region of the polypeptide chain contains a motor domain; M-type kinesins, where the middle region contains a motor domain; and C-type kinesins, where the carboxyl (-COOH) terminal region contains a motor domain.

[0007] KIF18A is a member of the N-type Kinesin-8 kinesin family. KIF18A protein is highly expressed in various tumors. Therefore, the development of KIF18A protein inhibitors may be a new breakthrough in cancer treatment. Summary of the Invention

[0008] In order to improve the prior art, the purpose of the present application is to provide a use of a KIF18A inhibitor in the preparation of a medicament for treating lung cancer (such as non-small cell lung cancer).

[0009] The purpose of the present application is achieved by the following technical solutions:

[0010] In one aspect, the present application provides a use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating lung cancer, wherein the structure of the compound 1 is as follows:

[0011] According to an embodiment of the present application, the pharmaceutically acceptable salt is selected from one or more of a sodium salt, a potassium salt, a hydrochloride salt, a p-toluenesulfonate salt, a maleate salt, and a methanesulfonate salt of the compound 1, and preferably a p-toluenesulfonate salt.

[0012] In another aspect, the present application provides a use of compound 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating lung cancer, wherein the structure of the compound 2 is as follows:

[0013] According to an embodiment of the present application, the pharmaceutically acceptable salt is selected from one or more of a sodium salt, a potassium salt, a hydrochloride salt, a p-toluenesulfonate salt, a maleate salt, and a methanesulfonate salt of the compound 2.

[0014] According to an embodiment of the present application, the medicament comprises a pharmaceutically acceptable carrier or excipient, and is suitable for preparation into an intravenous infusion, an intravenous drip, a subcutaneous administration, an intradermal administration, a muscle injection, an oral spray, an oral administration, a tumor in situ administration, or the like.

[0015] According to an embodiment of the present application, the medicament is prepared into an oral preparation, such as a tablet, a capsule, a pill, a granule, a solution, a suspension, a syrup, an injection (including an injection solution, a sterile powder for injection, or a concentrated solution for injection), a suppository, an inhalant, or a spray.

[0016] According to an embodiment of the present application, the medicament is administered orally.

[0017] According to an embodiment of the present application, the medicament is administered once a day or twice a day.

[0018] The present application also provides a method for preventing and / or treating lung cancer in a subject, comprising administering to the subject a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, or a composition containing compound 1 or a pharmaceutically acceptable salt thereof.

[0019] According to an embodiment of the present application, the pharmaceutically acceptable salt is selected from one or more than two of sodium salt, potassium salt, hydrochloride salt, p-toluenesulfonic acid salt, maleic acid salt and methanesulfonic acid salt of Compound 1, preferably p-toluenesulfonic acid salt.

[0020] The present application also provides a method for preventing and / or treating lung cancer disease in a subject, comprising administering to the subject a therapeutically effective amount of Compound 2 or a pharmaceutically acceptable salt thereof, or a composition comprising Compound 2 or a pharmaceutically acceptable salt thereof.

[0021] According to an embodiment of the present application, the pharmaceutically acceptable salt is selected from one or more than two of sodium salt, potassium salt, hydrochloride salt, p-toluenesulfonic acid salt, maleic acid salt and methanesulfonic acid salt of Compound 2.

[0022] According to an embodiment of the present application, the lung cancer is non-small cell lung cancer.

[0023] According to an embodiment of the present application, the non-small cell lung cancer is squamous cell carcinoma (squamous carcinoma), adenocarcinoma or large cell carcinoma.

[0024] According to an embodiment of the present application, the lung cancer is TP53-mutated non-small cell lung cancer.

[0025] According to an embodiment of the present application, the lung cancer is recurrent or metastatic advanced non-small cell lung cancer.

[0026] According to an embodiment of the present application, the Compound 1 or Compound 2, or a pharmaceutically acceptable salt thereof, or the composition is administered once daily or twice daily.

[0027] According to an embodiment of the present application, the Compound 1 or Compound 2, or a pharmaceutically acceptable salt thereof, or the composition is administered orally.

[0028] According to an embodiment of the present application, the Compound 1 or Compound 2, or a pharmaceutically acceptable salt thereof, is administered alone or in combination with other anti-tumor drugs.

[0029] According to an embodiment of the present application, the combination administration can be simultaneous or sequential administration.

[0030] According to an embodiment of the present application, the daily administration dose of the compound 1 or 2 is 0.1-1000 mg, which can be 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg.

[0031] According to an embodiment of the present application, the subject is a mammal, preferably a human.

[0032] The present application also provides a medicament for preventing and / or treating lung cancer disease in a subject, which is a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, or which is a composition containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, the structure of the compound 1 is as follows:

[0033] According to an embodiment of the present application, the pharmaceutically acceptable salt is selected from one or more of the sodium salt, potassium salt, hydrochloride salt, p-toluenesulfonic acid salt, maleic acid salt and methanesulfonic acid salt of compound 1, preferably the p-toluenesulfonic acid salt.

[0034] According to an embodiment of the present application, the compound 1 or the pharmaceutically acceptable salt thereof or the composition is administered orally.

[0035] The present application also provides a medicine for preventing and / or treating lung cancer disease in a subject, the medicine being a therapeutically effective amount of compound 2 or a pharmaceutically acceptable salt thereof, or the medicine being a composition containing a therapeutically effective amount of compound 2 or a pharmaceutically acceptable salt thereof, the structure of compound 2 being as follows:

[0036] Advantages of the present application:

[0037] The pharmacological experiment of the present application proves that compound 1 and compound 2 can inhibit the growth of non-small cell lung cancer heterogenous tumors. Compared with AMG650, the lower drug exposure of compound 1 and 2 can reduce the potential drug accumulation toxicity. It is shown that compound 1 and compound 2 have obvious therapeutic effect on non-small cell lung cancer. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 is a line graph showing the influence of tumor volume in HCC15 xenograft tumor model mice.

[0039] Figure 2 is a schematic diagram showing the tumor weight of HCC15 xenograft tumor model mice.

[0040] Figure 3 is a line graph showing the influence of body weight in HCC15 xenograft tumor model mice. DETAILED DESCRIPTION

[0041] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively described and explained the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of the present application.

[0042] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0043] The term "subject" herein refers to an animal, such as a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans.

[0044] The term "therapeutically effective amount" or "effective amount" herein refers to the amount of a compound disclosed and / or described herein that, when administered to a patient in need of such treatment, is sufficient to effect treatment as defined herein. The therapeutically effective amount of a compound can be an amount sufficient to treat a disease responsive to modulation (e.g., inhibition) of KIF18A or to treat non-small cell lung cancer. The therapeutically effective amount will vary depending on, for example, the subject and disease condition being treated, the subject's body weight and age, the severity of the disease condition, the particular compound, the dosing regimen to be followed, the timing of administration, the mode of administration, all of which can be readily determined by one of ordinary skill in the art.

[0045] The term "treatment" herein includes one or more of: inhibiting the disease or condition; slowing or arresting the development of a disease or condition; and / or relieving the disease or condition, that is, causing regression or remission of the disease or condition, and complete or partial reduction of the clinical symptoms of the disease or condition.

[0046] The term "therapeutic effect" herein refers to the effect caused by the treatment, which is manifested at the cellular level as the inhibition rate of cell growth or the mortality rate of cells, at the animal level as the change, usually the alleviation or improvement of the symptoms of the disease or disease condition, or the cure of the disease or disease condition.

[0047] The term "pharmaceutically acceptable salt" herein refers to the form of a compound in various pharmaceutically acceptable salts. If the compound has a basic center, it can form an acid addition salt; if the compound has an acidic center, it can form a base addition salt; if the compound contains both an acidic center and a basic center, it can also form an internal salt.

[0048] The specific preparation methods of Compound 1 and Compound 2 refer to the contents described in the patent documents of WO2024051755A1 and WO2024067675A1.

[0049] Example 1: Pharmacodynamic effect test of Compound 1 or Compound 2 on human non-small cell lung cancer HCC15 cell xenograft tumor mice

[0050] 1.1 Purpose of the experiment

[0051] To observe the therapeutic effect of Compound 1 or Compound 2 on human non-small cell lung cancer HCC15 cell xenograft tumor mice, evaluate its effect, and preliminarily explore its mechanism of action, and compare it with AMG650.

[0052] 1.2 Experimental materials

[0053] 1.2.1 Experimental reagents

[0054] 1.2.2 Experimental instruments

[0055] 1.3 Test drugs

[0056] AMG650, batch number: EB2302070-048P1; storage condition: 2-8℃; production and sample sending unit: Changchun Jin Sai Pharmaceutical Co., Ltd.

[0057] Compound 1, batch number: EB2302070-072P1; storage condition: 2-8℃; production and sample sending unit: Changchun Jin Sai Pharmaceutical Co., Ltd.

[0058] Compound 2, batch number: EB2214099-078P1; storage condition: 2-8℃; production and sample sending unit: Changchun Jin Sai Pharmaceutical Co., Ltd.

[0059] Solvent component: 20% PEG400 + 10% VE-TPGS + 70% aqueous solution containing 10% hydroxypropyl-β-cyclodextrin (HP-β-CD).

[0060] The preparation method is as follows: an appropriate amount of test sample is accurately weighed and placed in a suitable container, and the above solvent components are added step by step and ultrasonically vortexed, and a clear solution is obtained after each step before adding the next component. The final solution after preparation is a clear and transparent solution for administration.

[0061] The storage condition of the administration solution is that the preparation frequency is once a week, and each time after preparation, it is stored at -20℃. Before administration, it is placed at room temperature.

[0062] 1.4 Cell strain

[0063] Human non-small cell lung cancer cells HCC15 (item number ACC-496) were purchased from DSMZ.

[0064] 1.5 Experimental animals

[0065] Species and strain: Balb / c Nude mice.

[0066] Gender and age at arrival: female, 6-9 weeks old.

[0067] Source of animals: Beijing Vantoll Life Science and Technology Co., Ltd. Animal qualification certificate: 110011230106884731.

[0068] Rearing conditions: reared in polypropylene mouse boxes, with a maximum of 5 animals per box. Temperature: set temperature range 20-26℃, humidity: set humidity range 40%-70%, air changes: not less than 15 times of fresh air / hour, light: 12 hours of light and 12 hours of darkness alternately.

[0069] Establishment of animal models: human non-small cell lung cancer cells HCC15 were cultured in vitro, and the in vitro culture conditions were as follows: RPMI 1640 medium containing 10% fetal bovine serum (FBS) and 1% Antibiotic-Antimycotic (antibacterial-antifungal), temperature 37℃, and cultured in a 5% CO2 cell incubator. Routine medium replacement was performed twice a week, and cells in the logarithmic growth phase were collected for tumor inoculation. 0.2 mL of HCC15 tumor cell suspension (containing 10×10 6 cells) (PBS: Matrigel = 1:1) was inoculated subcutaneously on the right side of the neck and back of each mouse, and on the 17th day after cell inoculation, the average tumor volume reached 172mm3 At this time, the grouping of administration is started.

[0070] The experimental grouping is as follows:

[0071] According to the relevant regulations of animal welfare, if an individual experimental animal meets any of the following conditions during the experiment, the animal will be removed from the experimental group and euthanized. (1) The animal's body weight decreases by more than 20% compared to Day 0 (BWL≥20%) and is scheduled for euthanasia; (2) The animal has severe adverse reactions such as blindness, paralysis, etc.; (3) The tumor volume is greater than 2000mm 3 ; (4) Open ulcers form on the surface of the tumor.

[0072] After the last administration, blood was collected at different time points, and the collected whole blood was placed in a centrifuge tube containing K2-EDTA anticoagulant and centrifuged within 1 hour after collection (centrifugation conditions: 2-8℃, about 3200g for 10 minutes). After centrifugation, the supernatant plasma sample was used for PK analysis. After the last weighing at the end of the experiment, the remaining animals were euthanized and killed with CO2, and samples were collected and the tumors were weighed.

[0073] 1.6 Experimental observation indicators and detection methods

[0074] During the experiment, the animal body weight and tumor volume were measured twice a week, and the animal clinical symptoms were observed and recorded daily.

[0075] The tumor volume (TV) calculation formula is: 1 / 2×a×b 2 , where a and b are the length and width of the tumor measurement, respectively.

[0076] The tumor inhibition rate (%TGI TV ) calculation formula is: 1-(TV Tn -TV T0 ) / (TV Cn -TV C0 )*100%, TV C is the average tumor volume of the negative control group, TV T is the average tumor volume of the treatment group, TV T0 is the average tumor volume of the treatment group before administration, and TV C0 is the average tumor volume of the negative control group before administration.

[0077] The animal body weight change (%BWC) calculation formula is: (BW t -BW0) / BW0×100%, where BW t is the animal body weight at each measurement, and BW0 is the animal body weight at the time of grouping.

[0078] According to the Chinese NMPA "Technical Guidelines for Nonclinical Studies of Cytotoxic Antitumor Drugs" (November 2006), %T / C≤40% and P<0.05 by statistical analysis is effective. If the number of drug-related animal deaths exceeds 20%, the drug dose is considered to have serious toxicity.

[0079] 1.7 Statistical analysis

[0080] One-way ANOVA was used for inter-group comparison. No significant difference was considered when p>0.05, significant difference was considered when p<0.05, obvious significant difference was considered when p<0.01, and extremely significant difference was considered when p<0.001.

[0081] 1.8 Experimental results

[0082] As shown in Figure 1, the TGI of AMG650 30mg / kg was 97.95%, the TGI of compound 1 10mg / kg and 30mg / kg was 100.95% and 107.47% respectively, and the TGI of compound 2 20mg / kg and 60mg / kg was 98.52% and 108.54% respectively.

[0083] As shown in Figure 2, the tumor weight of the model group mice was 983±929mg, the tumor weight of AMG650 30mg / kg was 215±61mg, the tumor weight of compound 1 10mg / kg and 30mg / kg was 257±127mg and 164±71mg respectively, and the tumor weight of compound 2 20mg / kg and 60mg / kg was 204±121mg and 155±79mg respectively.

[0084] As shown in Figure 3, AMG650, compound 1 and compound 2 all dose groups had no significant effect on body weight changes relative to the solvent group animals, and no obvious toxicity was observed.

[0085] As shown in Table 1, the plasma exposure of compound 1 and compound 2 was much lower than that of AMG650, indicating that the drug had lower exposure under the same efficacy, which could reduce the potential drug accumulation toxicity.

[0086] Table 1 Comparison of plasma exposure in mice

[0087] In summary, in the HCC15 non-small cell lung cancer heterotransplanted mouse model, compound 1 and compound 2 significantly inhibited tumor growth, showing obvious therapeutic effect on non-small cell lung cancer.

[0088] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, and the like made within the spirit and principle of the present application should be included in the scope of protection of the present application.

Claims

1. Use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of lung cancer, wherein, The structure of the compound 1 is shown below: Preferably, the pharmaceutically acceptable salt is selected from one or more of sodium salt, potassium salt, hydrochloride, p-toluenesulfonate, maleate and methanesulfonate of the compound, preferably p-toluenesulfonate.

2. Use of Compound 2 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of lung cancer, wherein, The structure of the compound 2 is shown below: Preferably, the pharmaceutically acceptable salt is selected from one or more of sodium salt, potassium salt, hydrochloride, p-toluenesulfonate, maleate and methanesulfonate of the compound.

3. Use according to claim 1 or 2, wherein, The medicament comprises a pharmaceutically acceptable carrier or excipient, and is suitable for preparation into an intravenous infusion, intravenous drip, subcutaneous administration, intradermal administration, intramuscular injection, oral spray, oral administration, in situ administration to a tumor, etc., preferably the medicament is administered orally; more preferably, the medicament is administered once a day or twice a day.

4. Use according to claim 1 or 2, wherein, The medicament is prepared into an oral preparation, such as a tablet, a capsule, a pill, a granule, a solution, a suspension, a syrup, an injection, a suppository, an inhaler or a spray.

5. A method of preventing and / or treating lung cancer disease in a subject, wherein, The methods include administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a composition containing Compound 1, or a pharmaceutically acceptable salt thereof, the structure of which is shown below: Preferably, the pharmaceutically acceptable salt is selected from one or more of sodium salt, potassium salt, hydrochloride, p-toluenesulfonate, maleate and methanesulfonate of the compound, preferably p-toluenesulfonate; preferably, the compound 1 or a pharmaceutically acceptable salt thereof or the composition is administered orally.

6. A method of preventing and / or treating lung cancer disease in a subject, wherein, The method comprises administering to the subject a therapeutically effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, or a composition containing Compound 2, or a pharmaceutically acceptable salt thereof, the structure of which is shown below: Preferably, the pharmaceutically acceptable salt is selected from one or more of sodium salt, potassium salt, hydrochloride, p-toluenesulfonate, maleate and methanesulfonate of the compound.

7. The use according to any one of claims 1 to 4 or the method according to any one of claims 5 to 6, wherein, The lung cancer is non-small cell lung cancer, preferably the non-small cell lung cancer is squamous cell carcinoma, adenocarcinoma or large cell carcinoma; preferably, the lung cancer is TP53 mutant non-small cell lung cancer, preferably the lung cancer is recurrent or metastatic advanced non-small cell lung cancer.

8. The use according to any one of claims 1 to 4 or the method according to any one of claims 5 to 6, wherein, The compound 1 or compound 2, or a pharmaceutically acceptable salt thereof, is administered alone or in combination with other anti-tumor drugs, preferably the combination administration can be simultaneous or sequential administration. Preferably, the pharmaceutically acceptable salt is selected from one or more of sodium salt, potassium salt, hydrochloride, p-toluenesulfonate, maleate and methanesulfonate of the compound, preferably p-toluenesulfonate.

9. The use according to any one of claims 1 to 4 or the method according to any one of claims 5 to 6, wherein, The daily administration dose of the compound 1 or compound 2 is 0.1-1000 mg, which can be 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg.

10. The method of claim 5 or 6, wherein, The subject is a mammal, preferably a human.

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